Discovery and molecular characterization of a Bcl-2-regulated cell death pathway in schistosomes

Lee, EF; Clarke, OB; Evangelista, M; Feng, ZP; Speed, TP; Tchoubrieva, EB; Strasser, A; Kalinna, BH; Colman, PM; Fairlie, WD

Author(s): Lee, EF; Clarke, OB; Evangelista, M; Feng, ZP; Speed, TP; Tchoubrieva, EB; Strasser, A; Kalinna, BH; Colman, PM; Fairlie, WD;
Details: Publication Year 2011-04-26,Volume 108,Issue #17,Page 6999-7003
Journal Title: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Publication Type: Journal Article
Abstract: Schistosomiasis is an infectious disease caused by parasites of the phylum platyhelminthe. Here, we describe the identification and characterization of a Bcl-2-regulated apoptosis pathway in Schistosoma japonicum and S. mansoni. Genomic, biochemical, and cell-based mechanistic studies provide evidence for a tripartite pathway, similar to that in humans including BH3-only proteins that are inhibited by prosurvival Bcl-2-like molecules, and Bax/Bak-like proteins that facilitate mitochondrial outer-membrane permeabilization. Because Bcl-2 proteins have been successfully targeted with "BH3 mimetic" drugs, particularly in the treatment of cancer, we investigated whether schistosome apoptosis pathways could provide targets for future antischistosomal drug discovery efforts. Accordingly, we showed that a schistosome prosurvival protein, sjA, binds ABT-737, a well-characterized BH3 mimetic. A crystal structure of sjA bound to a BH3 peptide provides direct evidence for the feasibility of developing BH3 mimetics to target Bcl-2 prosurvival proteins in schistosomes, suggesting an alternative application for this class of drugs beyond cancer treatment.
Publisher: NATL ACAD SCIENCES
Keywords: BH3-ONLY PROTEINS; CAENORHABDITIS-ELEGANS; BCL-2 PROTEINS; BH3 DOMAINS; APOPTOSIS; FAMILY; INHIBITOR; GENOME; MCL-1; RECOGNITION
Link To PubMed Central Version: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3084110/
Publisher's Version: https://doi.org/10.1073/pnas.1100652108
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2011-04-26 12:00:00